Hereditary amyloidosis is rare and runs in families. That is to say, it is caused by inheritance of an abnormal copy of a gene, known as a mutation. These mutations lead to life long production of an amyloidogenic (amyloid-forming) variant of a normal protein. There are several different types, caused by mutations in different genes. The symptoms appear in adult life and often only in middle age or later. Some otherwise rare forms are common in a few geographic regions around the world, where a few families have intermarried over several generations.
Mutations in the genes for the following normal proteins may cause hereditary systemic amyloidosis, listed below in order from the most to the least common:
- transthyretin (TTR)- ATTR amyloid – over 100 known variants. ATTR amyloidosis is discussed in more detail here and patient information leaflets are available here.
- fibrinogen – AFib amyloid – patient information leaflet is available here.
- apolipoprotein AI – AApoAI amyloid
- apolipoprotein AII – AApoAII amyloid
- gelsolin – AGel amyloid
- lysozyme – ALys amyloid
- cystatin C – hereditary cerebral haemorrhage with amyloidosis, Icelandic type
- Aβ – hereditary cerebral haemorrhage with amyloidosis, Dutch type
- β2microglobulin – Aβ2m amyloid
Clinical features including organs affected by amyloid, age of disease onset and severity of disease differ widely both between :
- different hereditary amyloidosis types (where amyloid deposits contain different abnormal proteins)
- families with different mutations in the same gene, resulting in production of different abnormal variants of the same protein.
Disease manifestations may also differ between individuals with the same mutation producing identical variant proteins. Furthermore, not all individuals who inherit one of these mutations will actually develop clinical problems. Likewise, some people with a mutation develop only a small and insignificant amount of amyloid in their body while others seem to accumulate none at all. This is called incomplete penetrance, which is discussed in more detail here.